Introduction

Arterial hypertension or high blood pressure is considered as one of the most important public health problems which represents the principal risk factor of many cardiovascular diseases (Pickering, 1972). When not detected in the early stage, it may affect other organs and become associated with other diseases which may further aggravate the problem (Barst et al., 2004). Arterial hypertension is defined as a cardiorespiratory condition characterised by the persistent elevation of blood pressure in arteries. Blood pressure is measured in mmHg (millimetres of mercury) and the references values to diagnose high blood pressure are a systolic pressure of 140 mmHg or more and a diastolic pressure of 90 mmHg or more (Lawes et al., 2004). Furthermore, Lawes et al., (2004) argue that the principal risk factors for developing arterial hypertension are age, gender, life style, race or ethnicity and other conditions like diabetes and obesity.

The estimated prevalence of hypertension worldwide is approximately 1 billion people per year, and almost 7.1 million deaths per year are associated with high blood pressure (Chobanian et al., 2003). According to Kearney et al., (2004), the global prevalence of arterial hypertension differs around the world –  the lowest prevalence is registered in India: 3.4% for men and 6.8% for women and the highest prevalence in Poland with a prevalence of 68.8% in men and 72.5% in women. The author has focused on arterial hypertension because of the medical demand and complexity of the condition which from his personal experiences as a registered nurse in the emergency department of an international clinic in Angola, the condition is a major cause of morbidity and mortality. Pires et al., 2013 revealed that the prevalence of arterial hypertension in sub-Saharan Africa is 75 million with Angola having a very high rate and that effective treatments are needed. Due to the complexity of the treatment of arterial hypertension, the aim of this essay is to describe the use of angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers in the treatment of arterial hypertension, with a specific emphasis on pharmacological treatment of high blood pressure with captopril and Nifedipine.

The cardiovascular system or circulatory system is responsible for the circulation of blood in the body; blood is responsible for the transportation of nutrition and oxygen to all tissues. Components of the cardiovascular system includes the vessels and the heart. The heart works as a pump and the vessels are responsible for the transportation of blood enriched with oxygen and other nutrients to the tissues all over the body through the arteries and to bring back the blood laden with carbon dioxide (CO₂) through the veins  in order to be oxygenised  in the lungs via a process called haematosis (Lawes et al., 2004). Arterial blood pressure corresponds to the tension of  the blood  within the arteries as a result of the contractions (systole) and relaxation (diastole) of the heart; of which the  normal and conventional value in healthy people is around 120/80 mmHg (Humbert et al., 2004). The blood pressure depends directly on the cardiac output and peripheral vascular resistance. The cardiac output is the amount of blood that is pumped from the heart to the body for a period of 1 minute; corresponding to 5 litres of blood per minute in a healthy person weighing 70kg with a heart rate of 70beats per minute while peripheral vascular resistance is the resistance of vessel walls to the blood (Thomson et al., 1973).

The regulation of arterial blood pressure represents one of the most complex physiological functions of the organism to study and to understand because it depends on integrated actions of multiple systemic aspects including the cardiovascular, renal, neural and endocrine disorders (Chopra et al., 2011). Therefore, arterial hypertension is considered as a disease with multifactorial cause for its genesis (Judy et al., 1976; Sealey, 1990; Humbert et al., 2004; Kohan et al., 2011). For this reason, the investigation of its pathophysiology requires the knowledge of the mechanisms of how blood pressure is controlled in normal physiology before identifying the evidence of abnormalities that precede the elevation of blood pressure to pathologic levels. For blood pressure to occur, there must be a change in cardiac output and peripheral vascular resistance. The peripheral vascular resistance is the resistance of vessel walls to the blood (Glynn et al., 2010).

Blood pressure is regulated through neural or baroreceptor reflex, hormonal regulation (renin-angiotensin-aldosterone mechanisms), central and peripheric chemoreceptors and cardiopulmonary baroreceptors (Kohan et al., 2011). Neural system or baroreceptor reflex are reflexes that aim to maintain constant blood pressure through alterations in sympathetic and parasympathetic nervous system afferents (Chopra et al., 2011; Judy et al., 1976). This mechanism of blood pressure regulation is processed in three major steps: first is detection of arterial pressure by the baroreceptors found in the carotid sinus of the aortic arch. Baroreceptors are neurons which can detect and transmit neuronal stimulus about blood pressure to the brain. Secondly, the stimulus is sent to the brainstem by the vagus or glossopharyngeal nerve. Thirdly, integration of the sent stimulus in the solitary tract (alterations in the vasomotor centres) of the brainstem activates sympathetic (increases the cardiac frequency and the blood pressure and is associated with “fight or flight”) or parasympathetic (causing bradycardia and is associated with “rest and digest”) fibres depending on the arterial pressure alteration. Furthermore, the sympathetic fibres also act in the cardiac musculature increasing the contractility force of the heart therefore increasing the cardiac output and the blood pressure (Chopra et al., 2011). The sympathetic fibres also cause vasoconstriction of the arterioles and increase the total peripheral resistance (ibid). Furthermore, it also acts as vasoconstriction in the nervous  through the reduction of the non-stressed volume causing an increase of the stressed volume which may cause an increase of the arterial pressure (Glynn et al., 2010).

According to (Guyton, 1991) the central and peripheral chemoreceptors are also mechanisms of regulation of arterial pressure. These chemoreceptors serve the purpose to regulate the partial modification of carbon dioxide (central chemoreceptors) and the partial modification of oxygen (peripheral chemoreceptors). For example, in emergency situations when there is an elevated carbon dioxide pressure in the brain, central chemoreceptors increase blood flow to the brain by increasing peripheral vascular resistance causing vasodilation in the specific vascular bed of the central nervous system (ibid). In addition, blood pressure is also regulated through cardiopulmonary baroreceptors that detect changes in the blood flow mainly in the cardiac chambers and are related to the secretion of atrial natriuretic peptides – peptides secreted by the atrium and are related to the secretion of sodium and water that helps to regulate arterial pressure (Oliver et al., 1998).

Another  system of blood pressure regulation (which represents one of the focus of this essay) is the hormonal blood pressure system of regulation which comprises the renin-angiotensin- aldosterone system (RAAS).  According to Sealey, 1990 and Glynn et al., 2010, RAAS is a hormone system that regulates blood pressure that is detected by mechanoreceptors located in the renal arterioles; mechanoreceptors are responsible for capturing the signs of lowering blood pressure and sending the signals to the juxtaglomerular cells which produces, store and secrete renin. Renin is released into circulating plasma where it converts angiotensinogen formed by the liver into angiotensin I. The enzymatic action of ACE which are mainly found in the lungs and kidney transforms angiotensin I into angiotensin II. Angiotensin II causes vasoconstriction in the arterioles and the production of aldosterone that acting on the cortex above causes an increase of sodium (Na) and water (H₂O) absorption which increases blood volume and therefore, it increases blood pressure (Chopra et al., 2011; Glynn et al., 2010).

Many researches on heart conditions have indicated that the treatment of high blood pressure is essential   in reducing morbidity and mortality from cardiovascular disease (Peng et al., 2005; Weinberger, 1987). Therefore, there are a range of drugs developed and being developed to help control hypertension. ACE inhibitors and calcium channel blockers are included within the main classes of drugs that are normally used in antihypertensive therapy to control high blood pressure symptoms in patients.

ACE Inhibitors (Captopril)

ACE inhibitors are drugs widely used as valuable agents for the treatment of high blood pressure and other cardiovascular and renal problems (McMurray et al., 2003; Peng et al., 2005). The immediate protective effect of ACE inhibitors for the patients with hypertension or other heart disease is to block the conversion of angiotensin I to angiotensin II and kinin hydrolysis (Matchar et al., 2008; Peng et al., 2005). There are different classes of ACE inhibitors. They differ in their chemical structures from their active ingredients, potency, bioavailability, biological half-life, excretion pathway, distribution form and affinity for tissue-bound ACE, and whether they are administered as prodrugs (Brown and Vaughan, 1998). However, ACE inhibitors can be readily recognised by the common suffice ‘pril’. ACE inhibitors are classified into three major groups: Sulfhydryl-containing ACE inhibitors (e.g. captopril), dicarboxylate-containing ACE inhibitors (e.g. Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril and Benazepril) and phosphonate-containing ACE inhibitors (e.g. Fosinopril). Captopril is an example of the ACE inhibitors containing the sulfhydryl group which may confer on this drug other proprieties other than ACE inhibition including free-radical scavenging and effects on prostaglandins (M Campese and Lakdawala, 2015). However, the clinical relevance of these additional properties outside ACE inhibition remains a matter of research (Brown and Vaughan, 1998).

Captopril is an orally administered drug of the ACE group that is commonly used in the treatment of arterial hypertension and heart failure (Romankiewicz et al., 1983). This drug is the first representative of the group of drugs that inhibit ACE. Captopril acts in the body competing for the action of the ACE which is responsible for the conversion of angiotensin I into angiotensin II. In the treatment of essential hypertension, captopril is generally administered alongside other drugs, especially thiazide-type diuretics (Chobanian et al., 2003).

From a pharmacodynamic standpoint, as previously referenced, captopril as an ACE inhibitor and antihypertensive has the immediate action to nullify the effects of RAAS (Balakumar and Jagadesh, 2015). RAAS is one of the homeostatic mechanisms of the organism responsible for haemodynamic regulation, water and electrolyte balance at physiologically acceptable levels (Sealey, 1990). ACE is also an integral part of the enzymatic deactivation of bradykinin which is a vasodilator. The inhibition of the deactivation of bradykinin allows the increase of bradykinin which when sustained can cause the effects of increased vasodilation and consequently, the decrease of arterial blood pressure (Bönner, 1990).

There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein composed of a single polypeptide chain and is found in the blood and many other tissues; and the testicular isoform, which has a lower molecular mass compared to the somatic isoform and is found only in maturing spermatids and mature sperm and is considered to play a role in sperm maturation and sperm binding to the oviduct epithelium (Hagaman et al., 1998). The two functionally active domains of somatic ACE – N and C, have unique physiological functions due to the genetic tandem duplications, despite having immense sequence similarity (Drugbank, 2017). Domain C has been usually linked to blood pressure regulation whereas the N domain plays a role in the differentiation and proliferation of haematopoietic stem cells. ACE inhibitors bind to and inhibit the activity of both domains, but they are known to have greater affinity and inhibitory activity against the C domain.

The affinity of captopril for ACE is very high – approximately 30,000 times greater than that of angiotensin I (Gordon and Kittleson, 2008).  Unlike most other ACE inhibitors, captopril is not a prodrug, yet, its mechanism of action is to contend with angiotensin I to bind to ACE to inhibit an enzymatic conversion of angiotensin I to angiotensin II while concurrently inactivating the vasodilator peptide – bradykinin (Bönner, 1990; Gordon and Kittleson, 2008). Therefore, the decreasing levels of angiotensin II in tissues are responsible for lowering blood pressure by inhibiting the blood pressure effects of angiotensin II. Some evidence suggests that captopril also causes an increase in plasma renin activity due to the loss of inhibition of angiotensin II mediated by the feedback in the release of renin or stimulation of reflex mechanisms through baroreceptors (McElnay et al., 1995; Romankiewicz et al., 1983).

Regarding the absorption of captopril, 60-75% of the drug is absorbed in fasting individuals although food intake is responsible for a 25-40% reduction in absorption although some evidence shows that this reduction in absorption is not clinically relevant (Drugbank 2017a). The volume of distribution of captopril is 0.8L/kg (Duchin et al., 1988); regarding protein binding, captopril binds to proteins in the plasma, mainly albumin (25-30%) (Drugbank 2017a). The metabolism of captopril is hepatic and the main metabolites are captopril-cysteine disulphide and captopril disulphide dimer while the half-life of the drug is 1-2 hours (Sear 2013). Elimination of captopril from the body are hepatic and renal with half of the drug excreted unchanged and other half converted into inactive metabolites (Duchin et al., 1988; Sear 2013). However, overdose of captopril may cause toxicity which lead to symptoms such as emesis and decrease blood pressure (Joshi et al., 2010). Furthermore, the recognised side effects of captopril include dose-dependent rash, taste alterations, hypotension, gastric irritation, neutropenia, proteinuria, cough and angioedema (Joshi et al., 2010; Li et al., 2014).

Because of the recognised side effects, the use of captopril for the treatment of hypertension comes with some restrictions. The literature suggests that in aqueous medium, a solution of 2% captopril yields a pH value between 2.0 to 2.6 alongside a dissociation constant of 3.7±0.2, therefore it is suggested that the drug be stored in sealed enclosures even though it is quite stable up to a temperature 50°C (Tache et al., 2004). Also, for this reason, it is recommended that captopril should be taken one hour before meals and the dose should be individualised accordingly to the specific characteristics of the patients (Sear, 2013). These conditions regarding the use of captopril suggest that it is critical to take into consideration the history of the patient in regard to antihypertensive treatments including the extent of elevated blood pressure, salt restriction, and other clinical conditions. In some cases, it is also recommended to eliminate the antihypertensive medication that the patient was taking earlier, one week before starting treatment with captopril (Joshi et al., 2010). Furthermore, some literature suggests that in the treatment of arterial hypertension, the daily dose of captopril administration should not exceed 150 mg/day normally (ibid). However, in cases of patients suffering from severe hypertension (e.g. accelerated or malignant) in which temporary discontinuation of antihypertensive treatment is not feasible, captopril may be combined with a diuretic (ibid). Therefore, any other antihypertensive drugs may be given but the dosage of captopril should be initiated with a prescription of 25 mg two to three times daily with strict medical supervision (ibid).

Calcium Channel Blocker (Nifedipine)

Calcium channel blockers are another type of medications that are used to control high blood pressure. According to Weiner (1988), calcium channel blockers are a group of drugs that affect a range of cell in the body, exerting intense haemodynamic and electrophysiologic actions when used as treatments in various cardiovascular disorders. This type of medications are divided into two subgroups – the dihydropyridines that are mainly used in the treatment of angina and hypertension, and the rate-restricting calcium channel blockers that share the same proprieties but are also used to change the rate and the rhythm of the heart (Braunwald, 1982; Weiner, 1988; Li et al., 2015). The second group can be used in combination with other drugs to help in the treatment of atrial fibrillation (Weiner, 1988). Calcium channel blockers are drugs that act on muscle tone and peripheral vascular resistance by relaxing blood vessels (causing vasodilation). For example, verapamil and diltiazem acts best at the muscle tonus level (at rest when muscle contraction is low) whereas nifedipine and amlodipine acts at the peripheral vascular resistance level and these drugs are effective in the treatment of arterial hypertension (Scholz, 1997). The main cellular mechanism of calcium channels blockers are to prevent the entry of calcium ion (Ca⁺²) through calcium channels into electrically excitable cells (can be excited electrically to generate action potentials), including those of coronary and peripheral arterial smooth muscle and the heart (Ghosh and Greenberg, 1995; Li et al., 2015). The capacity of these drugs to block Ca⁺² entry into cells inhibits the principal role of this cation as an intracellular messenger (Ghosh and Greenberg, 1995; Li et al., 2015).

Nifedipine is a 1,4-dihydropyridine calcium channel blocker that acts as short and long acting agents (Snider et al., 2008). This drug acts mainly in cells of vascular smooth muscle stabilizing the L-type calcium channels controlling the arterial pressure in its inactive formation(Chen et al., 2015; Li et al., 2015). By preventing the influx of calcium into smooth muscle cells, nifedipine prevents Ca² dependent myocyte contraction and vasoconstriction. The other mechanism suggested for this drug’s vasodilatory capacity is associated with PH-dependent process of inhibiting Ca² influx through inhibiting carbonic anhydrase of smooth muscle (Drugbank, 2017b). Nifedipine is commonly used for the control of vasospastic angina, chronic stable angina, hypertension, and Raynaud’s phenomenon (ibid). It may also be used as a first line agent for left ventricular hypertrophy and isolated systolic hypertension (ibid).

Nifedipine is the first line drug of the dihydropyridine class of calcium channel blockers. It shares the same characteristics with other drugs of this group such as amlodipine, felodipine, isradipine, and nicardipine (Snider et al., 2008). In humans, there are five different types of voltage-gated calcium channels: L-type, N-type, P/Q-tpe, R-type, and T-type (Drugbank, 2017b). Calcium channel blockers act directly on L-type channels, which is the principal channel of cells that are involved in contraction. Like other dihydropyridine blockers, nifedipine binds directly to inactive calcium channels, stabilizing its inactive conformation (Snider et al., 2008). Since depolarizations of the smooth muscle arteries have longer duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells (ibid). Alternate splicing of the channel alpha-1 subunit gives additional arterial selectivity of nifedipine. In therapeutic sub-toxic concentrations, nifedipine has little effect on cardiac myocytes and conduction cells (Teja, 2011). By blocking calcium channels, nifedipine inhibits coronary artery spasm and dilates the systemic arteries, resulting in increased myocardial oxygen supply and decreased systemic blood pressure (Mueller, 1981; Teja, 2011).

Regarding the mechanisms of action of nifedipine, nifedipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through L-type calcium channels (Drugbank, 2017b; Snider et al., 2008). Calcium ions that enter the cell through L-type channels bind to calmodulin. The ensuing calcium-calmodulin complex activates myosin light chain kinase (MLCK) (Drugbank, 2017b). Activated MLCK prompts the phosphorylation of the regulatory light chain subunit of myosin, this step is critical in muscle contraction (ibid). The signals are then amplified by the release of calcium from the sarcoplasmic reticulum through ryanodine receptors (ibid). Inhibiting the initial influx of calcium prevents the contractile processes of smooth muscle cells thereby making the coronary and systemic arteries to be dilated, increasing oxygen supply to the cardiac muscle tissue, decreasing absolute peripheral resistance, reducing both systemic blood pressure and afterload (Drugbank, 2017b; Snider et al., 2008; Guazzi et al., 1977 ). The outcomes of these vasodilatory effects of nifedipine is a systemic reduction in blood pressure (Drugbank, 2017b). Furthermore, studies of Bakris et al., 1996 and Guazzi et al., 1977 found that nifidipine is a useful agent in the control of severe high blood pressure in emergencies and its efficacy in emergency situations makes it comparable with other medications that are commonly used in similar emergencies.

The protein binding of Nifedipine is of 92-98% and it is metabolised hepatically via cytochrome P450 (CYP) systems – mainly by CYP3A4, but also by CYP1A2 and CYP2A6 isozymes (Drugbank, 2017b; Haas et al., 2013). Nifedipine is normally metabolised to highly water-soluble, inactive metabolites accounting for 60 to 80% of the dose which is excreted in the urine (Drugbank, 2017b). Furthermore, the rest of the drug is excreted in faeces in metabolised form, perhaps because of biliary excretion (ibid). It has a half-life of approximately two hours (Challenor et al., 1986). However, like all the calcium channel blockers the main side effects of nifedipine are dizziness, nauseas, severe drop in blood pressure slurred speech and weakness (Challenor 1986; Snider 2008; Drugbank, 2017b).  Moreover, there are some less common side effects when using nifedipine such as rash, somnolence, and sometimes lower elevations of the functions of the livers (ibid). These side effects are of short duration and may be solve with dose adjustment (ibid).

Kancirová et al., (2016) found that combination of anti-high blood pressure drugs is effective for the management of hypertension. In their study, they found that compared to either captopril alone and nifedipine alone, in combined treatments, there was a significant impact of treatment on ATP synthase and there were no significant differences in fluidity of membrane.  It indicates that in treatment of high blood pressure using both captopril and nifedipine there is a non-competitive inhibition (Kancirová et al., 2016). However, the main advantages of Nifedipine include a quickly onset of action, increased cardiac output that help on decreasing the risk of collapse secondary to marked reduction in peripheral vascular resistance and effectiveness by the oral and sublingual routes (Diker et al., 1992; Guazzi et al., 1977; Snider et al., 2008).

According to Corea et al., (1983), compared to captopril, nifedipine tends to have a faster onset of action although this difference is not significant in long-term studies as mean cardiac index (CI) and pulmonary vascular resistance (PVR) do not show differences in relation to the control of arterial pressure using the two drugs. Whereas stroke index (SI) and ejection fraction (EF) were higher in captopril, plasma noradrenaline concentration and heart rate (HR) were lower in captopril than in nifedipine (ibid). Although in acute management, blood pressure seems to be similar in both drugs (ibid). This suggests that in high blood pressure treatment, nifedipine is effective in achieving a very rapid haemodynamic response and captopril is more appropriate in long-term management. Similarly, sublingual captopril and nifedipine administration have been shown to be similarly effective for the management of high blood pressure after abdominal aortic surgery (Leeman and Degaute, 1995). However, nifedipine may cause a deterioration in pulmonary gas exchange (ibid). Moreover, Gemici et al. (1999) argue that sublingual administration of nifedipine 10 mg and captopril 25 mg are not different in terms of their anti-high blood pressure effect. However, there may be a significant drop in the HR in the patients taking captopril, but not in the patients taking nifedipine. Sublingual captopril is as effective as, and has less side effects than sublingual nifedipine. Therefore, because sublingual captopril has fewer side effects, it may be safer than nifedipine in the treatment of hypertensive crisis (Gemici et al., 1999).

Conclusion

To conclude, the combination of multiple evidence show that arterial hypertension represents a serious public health problem in the world and is among the principal risk factors for many cardiovascular diseases. Due to the complexity of the disease, there are a wide range of drugs used to control the elevation of the blood pressure. Among them is captopril, an ACE inhibitor and nifedipine, a calcium channel blocker. Both drugs are administered orally and share almost the same half-life. Many researches demonstrated that these two drugs are effective to control in short- and long-term hypertension. However, they do not share identical characteristics and have got different mechanisms of action. Nifedipine compared to captopril tends to have a faster onset of action. In high blood pressure management, nifedipine is effective in achieving a very rapid haemodynamic response and captopril is more appropriate in long-term management. Because of the eventual side effects of these drugs, captopril and nifedipine should be administered with strict control of a health care professional mainly physicians, pharmacists and nurses.